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User:Cellular Biochemistry II/Course 2010/FGD1

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FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 (Rho/Rac GEF) is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome.[1] Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans.[2]

FGD1 is a guanine-nucleotide exchange factor (GEF), that can activate the Rho GTPase Cdc42. It localizes preferentially to the trans-Golgi network (TGN) of mammalian cells and regulates for example the secretory transport of bone-specific proteins from the Golgi complex. Thus Cdc42 and FGD1 regulate secretory membrane trafficking that occurs especially during bone growth and mineralization in humans.[3] FGD1 promotes the nucleotide exchange on the GTPase Cdc42, a key player in the establishment of cell polarity in all eukaryotic cells. The GEF activity of FGD1, causing the activation of Cdc42, is harbored in its DH domain and causes the formation of filopodia, the cells to migrate. FGD1 activates also c-Jun N-terminal kinase (JNK) signaling cascade, important in cell differentiation and apoptosis.[4] It also promotes the transitition through G1 during the cell cycle and causes tumorgenic transformation of NIH/3T3 fibroblasts.[5][6]

The FGD1 gene is located on the short arm of the X-chromosome and is essential for normal mammalian embryonic development. Mice embryos that carried experimentally introduced mutations in the FGD1 gene had skeletal abnormalities affecting bone size, cartilage growth, vertebrae formation and distal extremities.[4] These severe phenotypes are consistent with a lack of Cdc42 activity, as it controls membrane traffic as well as the organization of the actin cytoskeleton.[7] Mutations in the FGD1 gene that cause the production of non-functional proteins are responsible for the severe phenotype of the X-linked disorder faciogential dysplasia (FGDY), also called Aarskog-Scott syndrome.

Structure

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The mature human protein contains several characteristic motifs and domains that are involved in the protein´s function. The 951 amino acid long protein has an approximate size of 106kDa. A proline-rich stretch, predicted to encode two partially overlapping src homology 3 (SH3)-binding domains, stretches from amino acid 7 – 330, a DH domain (DBL homology domain), which harbors the GEF enzymatic activity, lies between the residue 373 – 561, a first PH domain between residues 590 – 689, a FYVE zinc finger domain (named after the four proteins it was found in Fab1, YOTB, Vac1, and EEA1) between residues 730 – 790, and a second PH domain between residues 821 – 921.[8]

The DH domain is required for the activation of Cdc42, namely the catalytic exchange of GDP with GTP on Cdc42, while the PH domains confer membrane binding. The prolin-rich domain interacts with cortactin and actin-binding protein 1.[3][9] FYVE-finger domains are conserved through evolution and often involved in membrane trafficking (e.g. Vac1p, Vps27p, Fab1, Hrs-2). One class of these domains was shown to bind selectively to phosphatidylinositol 3-phosphate. PH domains are known to specifically bind to polyphosphoinositides and influence the enzymatic activity of the GEF they are located in.[10]

Function

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FGD1 activates Cdc42 by exchanging GDP bound to Cdc42 for GTP and regulates the recruitment of Cdc42 to Golgi membranes. Levels of both FGD1 and Cdc42 are enriched on the Golgi complex itself and their interdependence regulates the transport of cargo proteins from the Golgi. FGD1 and Cdc42 colocalize in the trans-Golgi network. FGD1 inhibition has an inhibitory effect on post-Golgi transport.[3] Another interaction partner of FGD1 is cortactin, which is directly bound by the prolin-rich domain of FGD1. As cortactin is known to promote actin polymerization by the Arp2/3 complex, this interaction seems to promote actin assembly.[7]

FGD1 is also transiently associated with and required for the formation of membrane protrusions on invasive tumor cells.[9]

Tissue distribution

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Human FGD1 is expressed predominantly in fetal tissues of brain and kidney, but also present in the heart and lung. It is hardly detectable in the corresponding adult tissues. FGD1 is expressed in areas of bone formation and postnatally in skeletal tissue, the perichondrium, joint capsule fibroblasts and resting chondrocytes.[3][1]

Clinical signifance

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Mutations in the FGD1 gene cause phenotypes associated with the X-linked recessively transmitted faciogential dysplasia (FGDY) also know as Aarskog-Scott syndrome, a human developmental disorder that can occur with neurologial problems.[1]

The disease phenotypes are due to improper bone formation and is more often seen in males though the severity depends on age. Mutations in the FGD1 gene are randomly distributed in all the domains of the protein product, modifying the intracellular localization and/or the GEF catalytic activity of FGD1.[8][11][12][13] Up to 2010 twenty distinct mutations have been reported, including three missense mutations (R402Q; S558W; K748E), four truncating mutations (Y530X; R656X; 806delC; 1620delC), one in-frame deletion (2020_2022delGAG) and the first reported splice site mutation (1935þ3A→C).[14]

Increased expression of FGD1 correlates with tumor aggressiveness in prostate and breast cancer, linking the protein to cancer progression.[9]

See also

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References

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  1. ^ a b c Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, Stevenson RE, Glover TW, Wilroy RS, Gorski JL (November 1994). "Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor". Cell. 79 (4): 669–78. doi:10.1016/0092-8674(94)90552-5. PMID 7954831.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  2. ^ Gao J, Estrada L, Cho S, Ellis RE, Gorski JL (December 2001). "The Caenorhabditis elegans homolog of FGD1, the human Cdc42 GEF gene responsible for faciogenital dysplasia, is critical for excretory cell morphogenesis". Hum. Mol. Genet. 10 (26): 3049–62. doi:10.1093/hmg/10.26.3049. PMID 11751687.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  3. ^ a b c d Egorov MV, Capestrano M, Vorontsova OA, Di Pentima A, Egorova AV, Mariggiò S, Ayala MI, Tetè S, Gorski JL, Luini A, Buccione R, Polishchuk RS (May 2009). "Faciogenital Dysplasia Protein (FGD1) Regulates Export of Cargo Proteins from the Golgi Complex via Cdc42 Activation". Mol. Biol. Cell. 20 (9): 2413–27. doi:10.1091/mbc.E08-11-1136. PMC 2675621. PMID 19261807.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  4. ^ a b Olson MF, Pasteris NG, Gorski JL, Hall A (December 1996). "Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases". Curr. Biol. 6 (12): 1628–33. doi:10.1016/S0960-9822(02)70786-0. PMID 8994827.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  5. ^ Nagata K, Driessens M, Lamarche N, Gorski JL, Hall A (June 1998). "Activation of G1 progression, JNK mitogen-activated protein kinase, and actin filament assembly by the exchange factor FGD1". J. Biol. Chem. 273 (25): 15453–7. doi:10.1074/jbc.273.25.15453. PMID 9624130.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  6. ^ Whitehead IP, Abe K, Gorski JL, Der CJ (August 1998). "CDC42 and FGD1 Cause Distinct Signaling and Transforming Activities". Mol. Cell. Biol. 18 (8): 4689–97. doi:10.1128/MCB.18.8.4689. PMC 109055. PMID 9671479.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  7. ^ a b Etienne-Manneville S (March 2004). "Cdc42--the centre of polarity". J. Cell. Sci. 117 (Pt 8): 1291–300. doi:10.1242/jcs.01115. PMID 15020669.{{cite journal}}: CS1 maint: date and year (link)
  8. ^ a b Orrico A, Galli L, Falciani M, Bracci M, Cavaliere ML, Rinaldi MM, Musacchio A, Sorrentino V (August 2000). "A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome)". FEBS Lett. 478 (3): 216–20. doi:10.1016/S0014-5793(00)01857-3. PMID 10930571.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  9. ^ a b c Ayala I, Giacchetti G, Caldieri G, Attanasio F, Mariggiò S, Tetè S, Polishchuk R, Castronovo V, Buccione R (February 2009). "Faciogenital dysplasia protein Fgd1 regulates invadopodia biogenesis and extracellular matrix degradation and is up-regulated in prostate and breast cancer". Cancer Res. 69 (3): 747–52. doi:10.1158/0008-5472.CAN-08-1980. PMID 19141649.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  10. ^ Estrada L, Caron E, Gorski JL (March 2001). "Fgd1, the Cdc42 guanine nucleotide exchange factor responsible for faciogenital dysplasia, is localized to the subcortical actin cytoskeleton and Golgi membrane". Hum. Mol. Genet. 10 (5): 485–95. doi:10.1093/hmg/10.5.485. PMID 11181572.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  11. ^ Bedoyan JK, Friez MJ, DuPont B, Ahmad A (2009). "First case of deletion of the faciogenital dysplasia 1 (FGD1) gene in a patient with Aarskog-Scott syndrome". Eur J Med Genet. 52 (4): 262–4. doi:10.1016/j.ejmg.2008.12.001. PMID 19110080.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Orrico A, Galli L, Cavaliere ML, Garavelli L, Fryns JP, Crushell E, Rinaldi MM, Medeira A, Sorrentino V (January 2004). "Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients". Eur. J. Hum. Genet. 12 (1): 16–23. doi:10.1038/sj.ejhg.5201081. PMID 14560308.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  13. ^ Schwartz CE, Gillessen-Kaesbach G, May M, Cappa M, Gorski J, Steindl K, Neri G (November 2000). "Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome". Eur. J. Hum. Genet. 8 (11): 869–74. doi:10.1038/sj.ejhg.5200553. PMID 11093277.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  14. ^ Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, Hertz JM, Jacquemont S, Taurisano R, Arroyo Carrera I, Tarantino E, Devriendt K, Melis D, Thelle T, Meinhardt U, Sorrentino V (February 2010). "Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene". Am. J. Med. Genet. A. 152A (2): 313–8. doi:10.1002/ajmg.a.33199. PMID 20082460.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
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